A vast number of signaling systems have been shown to be regulated by heterotrimeric guanine nucleotide binding regulatory proteins (G proteins). Cellular processes controlled through G protein action including hormone, neurotransmitter and growth factor action, and these G proteins have also been implicated in intracellular membrane trafficking and secretion. The broad goal of the research proposed in this application is to understand the molecular mechanisms of how G proteins function in cellular signaling pathways. The proposed research centers on elucidating the signaling pathways controlled by a specific member of the G protein family termed Gaz. Gaz is a G protein predominately found in neuronal and neuroendocrine cells. Through application of an interaction cloning strategy, several proteins were identified that specifically interacted with the activated form of Gaz. These findings led to the uncovering of two potentially interconnected cellular processes under control of this G protein. The first of these is a MAP kinase pathway important in neuronal differentiation. Activation of Gaz negatively regulates this pathway through the ability to recruit a regulator of the Rap1 GTPase, termed Rap1 GAP, to the cellular location where it can act on Rap1. The second process involves a Gaz-selective member of the RGS family, termed RGSZ1, that interacts with both activated Gaz and a member of the stathmin family of microtubule regulators termed SCG10. In this next funding period, we will employ a variety of biochemical, molecular, and cellular techniques to study pathways controlled by Gaz in a concerted effort to ascertain the functional consequences of Gz activation. Much of this work will be performed in pancreatic ?-cells, which we have found contain all the identified components in Gz signaling pathways. In addition, we have obtained very exciting data that Gaz activation both inhibits glucose- stimulated insulin secretion and impacts on signaling pathways important in proliferation and survival in these cells. Given the evidence for the importance of G protein-coupled signaling pathways in regulation of multiple aspects of islet cell biology, these data point to important roles for Gz in the physiology, and possible pathophysiology, of pancreatic ?-cells. ? ? ?
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